PEPTIDE ANTAGONISTS TO TGF-BETA AS ANTITHROMBOTIC AGENTS

PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1) HAS BEEN IMPLICATED AS A POTENTIAL RISK FACTOR FOR MYOCARDIAL INFARCTION AND AS AN INHIBITOR OF PHARMACOLOGICAL THROMBOLYSIS. TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA), A MAJOR CONSTITUENT OF PLATELET LYSATES, INDUCES PAI-1 RELEASE FROM VASCULAR ENDOTHELIAL CELLS. THE LONG-TERM OBJECTIVE OF THE RESEARCH IS TO DEVELOP A PEPTIDE ANTAGONIST OF TGF-BETA AND TO VALIDATE ITS UTILITY FOR ADJUNCTIVE THERAPY TO PHARMACOLOGICAL THROMBOLYSIS AND/OR CHRONIC THERAPY OF PATIENTS, WITH ELEVATED LEVELS OF PAI-1. SPECIFICALLY, THE STUDIES WILL: 1) VERIFY THAT RN10031, A PEPTIDE ANTAGONIST OF TGF-BETA, INHIBITS TGF-BETA-INDUCED PAI-1 RELEASE FROM VASCULAR ENDOTHELIAL CELLS, AND 2) IDENTIFY STRUCTURE/ACTIVITY RELATIONSHIPS CRITICAL TO RN10031 WHICH WILL ALLOW OPTIMIZATION OF ITS ACTIVITY, RN10031, A 22 AMINO ACID PEPTIDE, AND ANALOGUES THEREOF WILL BE TESTED FOR THEIR ABILITY TO BLOCK PAI-1 RELEASE (MEASURE IMMUNOCHEMICALLY) FROM HUMAN VASCULAR ENDOTHELIAL CELLS STIMULATED WITH VARYING CONCENTRATIONS OF HUMAN PLATELET DERIVED TGF-BETA. APPROXIMATELY 30 ANALOGUES WILL BE PREPARED TO IDENTIFY RESIDUES OF THE RN10031 PEPTIDE CRITICAL FOR ITS ANTAGONIST ACTIVITY. IT IS CLAIMED THAT SPECIFIC, POTENT TGF-BETA ANTAGONISTS OFFER THE POTENTIAL FOR DEVELOPMENT OF A NEW CLASS OF DRUGS WHICH REGULATE FIBRINOLYSIS.